ABCMdb

PMID: 8651290

Feigenbaum V, Lombard-Platet G, Guidoux S, Sarde CO, Mandel JL, Aubourg P
Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy.
Am J Hum Genet. 1996 Jun;58(6):1135-44., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCD1 p.Pro560Leu Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Login to comment 58 ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Arg518Trp ABCD1 p.Ser98Leu Twenty-nine different mutations were found, and five of them were present in more than one family (S98L, R518W, and R660W in two families, and 1801 delAG and P560L in four families each). Login to comment 59 ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Arg518Trp ABCD1 p.Ser98Leu Twenty-nine different mutations were found, and five of them were present in more than one family (S98L, R518W, and R660W in two families, and 1801 delAG and P560L in four families each). Login to comment 75 ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Arg660Trp ABCD1 p.Arg518Trp ABCD1 p.Arg518Trp ABCD1 p.Gly116Arg ABCD1 p.Ser108Trp ABCD1 p.Asn148Ser ABCD1 p.Arg152Cys ABCD1 p.Gly512Ser ABCD1 p.Asp221Gly ABCD1 p.Ala294Thr ABCD1 p.Ser606Pro ABCD1 p.Tyr181Cys ABCD1 p.Asp200Val 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic. Login to comment 76 ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Arg660Trp ABCD1 p.Arg518Trp ABCD1 p.Arg518Trp ABCD1 p.Gly116Arg ABCD1 p.Ser108Trp ABCD1 p.Asn148Ser ABCD1 p.Arg152Cys ABCD1 p.Gly512Ser ABCD1 p.Asp221Gly ABCD1 p.Ala294Thr ABCD1 p.Ser606Pro ABCD1 p.Tyr181Cys ABCD1 p.Asp200Val 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic. Login to comment 87 ABCD1 p.Arg152Cys C, ALD fibroblasts (R152C mutation) immunostained with mAb2B4, showing normal ALDP immunoreactivity. Login to comment 88 ABCD1 p.Pro560Leu ABCD1 p.Arg152Cys C, ALD fibroblasts (R152C mutation) immunostained with mAb2B4, showing normal ALDP immunoreactivity. Login to comment 89 ABCD1 p.Pro560Leu D, ALD fibroblasts (P560L mutation), showing weakly positive immunoreactivity with mAb 2B4 (and 1D6, not shown). Login to comment 91 ABCD1 p.Arg660Trp F, ALD white blood cells (R660W mutation) immunostained with mAb 2B4, showing the absence of ALDP immunoreactivity. Login to comment 92 ABCD1 p.Arg660Trp ABCD1 p.Asp221Gly F, ALD white blood cells (R660W mutation) immunostained with mAb 2B4, showing the absence of ALDP immunoreactivity. Login to comment 93 ABCD1 p.Asp221Gly G and H, fibroblasts and white blood cells of heterozygous women (D221G mutation) immunostained with mAb 1D6 in panel G and 2B4 in panel H. Arrows in panel H show a monocyte with a complete absence of ALDP immunoreactivity close to a monocyte with normal ALDP immunoreactivity. Login to comment 100 ABCD1 p.Ser98Leu ABCD1 p.Arg152Cys Double staining with anti-ALDP and anticatalase was performed in two ALD fibroblast lines with normal ALDP immunocytofluorescence (S98L and R152C mutants). Login to comment 102 ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Arg518Trp Variation in the immunoreactivity of the ALD mutant protein was observed for two mutations, P560L and R518W: immunoreactivity of mutant protein P560L was markedly decreased in fibroblasts and peripheral white blood cells from patients 69, 5, and 37 and was completely absent in patient 13. Login to comment 104 ABCD1 p.Arg518Trp Similarly, ALDP immunoreactivity of mutant protein R518W was markedly decreased in fibroblasts from patient 76 and completely absent in fibroblasts from another patient (73) with the same mutation. Login to comment 131 ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Ser98Leu ABCD1 p.Gly116Arg ABCD1 p.Gly116Arg ABCD1 p.Ser108Trp ABCD1 p.Gly512Ser ABCD1 p.Asp221Gly ABCD1 p.Asp221Gly ABCD1 p.Ser606Pro ABCD1 p.Pro263Leu ABCD1 p.Gly522Trp Lane 1, protein markers; lane 2, control; lane 3, patient 18 (S108W); lane 4, patient 32 (P263L); lane 5, patient 5 (P560L); lane 6, patient 4 (G116R); lane 7, patient 19 (D221G); lane 8, patient 33 (S98L); lane 9, patient 78 (S606P); lane 10, patient 3 (no mutation found); lane 11, patient 37 (P560L); lane 12, patient 22 (R660W); lane 13, control; lane 14, patient 39 (T1051); lane 15, patient 4 (G116R); lane 16, patient 43 (frameshift at Y180); lane 17, patient 5 (P560L); lane 18, patient 59 (G512S); lane 19, patient 29 (frameshift at D649); lane 20, patient 69 (P560L); lane 21, patient 19 (D221G); lane 22, patient 64 (W1OX); lane 23, patient 63 (frameshift at R231); lane 24, patient 52 (no mutation found); lane 25, patient 61 (frameshift at E471); and lane 26, patient 83 (G522W). Login to comment 134 ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Arg518Trp ABCD1 p.Ser98Leu Exceptions are a dinucleotide deletion (del 1801-1802) and P560L missense mutation, which were both observed in four kindreds, and S98L, R518W, and R660W missense mutations, which were each observed in two kindreds. Login to comment 135 ABCD1 p.Pro560Leu As shown in ALD Dutch families (Kemp et al. 1994), there is no indication that the French ALD families in whom the dinucleotide deletion (del 1801-1802) or the P560L mutation was observed were related. Login to comment 140 ABCD1 p.Pro560Leu ABCD1 p.Arg660Trp ABCD1 p.Arg518Trp ABCD1 p.Ser98Leu In all cases, only one alteration was found, and except for the S98L, R518W, P560L, and R660W mutations, these alterations differed from each other. Login to comment 142 ABCD1 p.Pro560Leu ABCD1 p.Arg518Trp ABCD1 p.Arg518Trp The R518W mutation occurred as a de novo mutation in one ALD patient, and the R518W and P560L mutations were not observed in 100 normal X chromosomes. Login to comment 144 ABCD1 p.Arg518Trp ABCD1 p.Gly512Ser ABCD1 p.Ser606Pro ABCD1 p.Gly522Trp Four missense mutations (G512S, R518W, G522W, and S606P) were found in the ATP-binding domain. Login to comment 145 ABCD1 p.Gly512Ser ABCD1 p.Ser606Pro ABCD1 p.Gly522Trp Three of these mutations (G512S, G522W, and S606P) affect amino acid residues that are identical among other ABC transporters (see fig. 4 in Mosser et al. 1993 and fig. 1 in Fanen et al. 1994). Login to comment 146 ABCD1 p.Ala294Thr One missense mutation (A294T) was found in an EAA-like motif that is highly conserved in ALDP, ALDPR, and PMP70 proteins (Shani et al. 1995) and whose mutations can cause loss of transporter function of an ABC protein (Koster and Braun 1992). Login to comment 147 ABCD1 p.Asp221Gly ABCD1 p.Tyr181Cys ABCD2 p.Asp200Val One mutation (Y181C) was found in the loop between the third and fourth transmembrane domain, and two mutations (D200V and D221G) were found in the third transmembrane domain. Login to comment 171 ABCD1 p.Asp221Gly ABCD1 p.Tyr181Cys Another possibility is that some of these mutations (in particular, Y181C, D220V, and D221G) may affect the targeting of ALDP into peroxisomal membrane. Login to comment 172 ABCD1 p.Gly512Ser ABCD1 p.Asp221Gly ABCD1 p.Ser606Pro ABCD1 p.Tyr181Cys ABCD1 p.Gly522Trp Missense mutations leading to a lack of ALDP included three mutations located in the ATP-binding domain (G512S, G522W, and S606P). Login to comment 173 ABCD1 p.Pro560Leu ABCD1 p.Arg518Trp ABCD1 p.Ser108Trp ABCD1 p.Gly512Ser ABCD1 p.Ser606Pro ABCD1 p.Pro263Leu ABCD1 p.Gly522Trp Four missense mutations (S108W, P263L, R518W, and P560L) resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP. Login to comment 174 ABCD1 p.Pro560Leu ABCD1 p.Arg518Trp ABCD1 p.Ser98Leu ABCD1 p.Ser108Trp ABCD1 p.Asn148Ser ABCD1 p.Arg152Cys ABCD1 p.Pro263Leu Three missense mutations (S98L, N148S, and R152C) resulted in the synthesis of a stable but presumably nonfunctioning protein. Login to comment 175 ABCD1 p.Ser98Leu ABCD1 p.Asn148Ser ABCD1 p.Arg152Cys Three missense mutations (S98L, N148S, and R152C) resulted in the synthesis of a stable but presumably nonfunctioning protein. Login to comment